Large conductance calcium activated channels are broadly expressed in neurons and muscle where they modulate cellular activity and function. Decades of research support an ongoing interest in modulating large conductance Ca2+ activated K+ (BK) channel function to alter disease states.
Age-related hearing loss (ARHL) is a widespread medical problem affecting approximately 30-40% of people 65 and older, while >50% of people 75 and older have difficulty hearing. The primary etiology of ARHL is two-fold, i) a loss in sensitivity to sound resulting from functional deficits in inner ear transduction and ii) alteration in central auditory processing within the brain. Deficits at the inner ear raise the threshold for how a loud a sound must be to be heard, particularly for higher pitched sounds. Many consonances are high-pitched sounds, making this deficit directly interfere with one's ability to understand speech. These types of hearing deficits can be improved with current hearing aid technology, although some patients may resist wearing hearing aids. Much more difficult to improve with hearing aids is the functional loss in the brain's ability to process sounds. These central auditory processing deficits make it very difficult to understand speech in a noisy environment.
The large conductance calcium-activated potassium (BK) channel is a promising pharmacological target. Widely expressed in human tissue where it is gated by voltage and intracellular calcium, the BK channel regulates smooth muscle tone, endocrine secretion and neuronal excitability. Despite broad expression, global knockout of the constitutive pore-forming a subunit is not lethal in mice. In Caenorhabditis elegans and Drosophila, null mutations in the highly conserved invertebrate BKα channel reduces acute ethanol intoxication and tolerance.
Restriction of BK channel function has therapeutic value in human disease. Human tumor growth and metastasis is supported by higher BK channel expression and curtailed by BK channel blockers. In the CNS, a BK channel gain-of-function mutation is associated with an increased risk for epilepsy in humans and mice, and blocking BK channel function suppresses seizure activity in vivo and in vitro. BK channels are expressed throughout the auditory system where they maintain high frequency firing. Thus, suppression of BK channel function in the inferior colliculus (IC) may restrict audiogenic seizures, which originate in this region. A reduction in high frequency firing in the IC could also reduce tinnitus or “ringing in the ears.” Evidence from animal models of tinnitus suggests that a focal loss of output from the cochlea, common in many cases of tinnitus, in turn suppresses inhibitory drive in the central auditory system resulting in hyperexcitability. This neuronal hyperexcitability is evident in both the cochlear nucleus and at the level of the IC.
A number of peptides alter BK channel function. Peptide scorpio- or conotoxins block the pore with low nanomolar affinity and high specificity but have relatively complex structures restricting large-scale synthesis. Small, endogenous peptides or peptide fragments modulate BK channel function, but mainly act with lower affinity. For example, fragments of a BK channel auxiliary subunit (β2) inactivate currents in the micromolar range. There are currently no BK channel-directed peptides for CNS pharmacological applications, having high affinity and specificity, blood-brain barrier (BBB) permeability and amenability to large-scale synthesis.